Partial control of HIV occurs during acute infection, although the mechanisms responsible are poorly understood. We studied the ability of antibody-dependent cellular cytotoxicity (ADCC) antibodies in serum to activate natural killer (NK) cells in longitudinal samples from 8 subjects with well-defined early HIV infection who controlled viremia to low levels. NK cell activation by ADCC antibodies to gp140 Env proteins was detected in half of the subjects at the first time point studied, a mean of 111 d after the estimated time of infection. In contrast, ADCC-mediated NK cell activation in response to linear HIV peptides evolved more slowly, over the first 2 y of infection. Our studies suggest that HIV-specific ADCC responses to conformational epitopes occur early during acute HIV infection, and broaden to include linear epitopes over time. These findings have implications for the immune control of HIV.